Role of cAMP in the promotion of colorectal cancer cell growth by prostaglandin E2

BMC Cancer. 2008 Dec 19;8:380. doi: 10.1186/1471-2407-8-380.

Abstract

Background: Prostaglandin E2 (PGE2), a product of the cyclooxygenase (COX) reaction, stimulates the growth of colonic epithelial cells. It is inferred that the abrogation of prostaglandins' growth-promoting effects as a result of COX inhibition underlies the advantageous effects of non-steroidal anti-inflammatory drugs in colorectal carcinoma (CRC). Despite this appreciation, the underlying molecular mechanisms remain obscure since cell culture studies have yielded discrepant results regarding PGE2's mitogenicity.

Methods: We have employed several alternative approaches to score cell proliferation and apoptosis of 4 CRC cell lines exposed to PGE2 under various conditions. To investigate the role of cAMP in PGE2's functions, activation of the cAMP pathway was assessed at different levels (changes in cAMP levels and PKA activity) in cells subjected to specific manipulations including the use of specific inhibitors or prostanoid receptor-selective agonists/antagonists.

Results: Our data document that the dose-response curve to PGE2 is 'bell-shaped', with nano molar concentrations of PGE2 being more mitogenic than micro molar doses. Remarkably, mitogenicity inversely correlates with the ability of PGE2 doses to raise cAMP levels. Consistent with a major role for cAMP, cAMP raising agents and pertussis toxin revert the mitogenic response to PGE2. Accordingly, use of prostanoid receptor-selective agonists argues for the involvement of the EP3 receptor and serum deprivation of HT29 CRC cells specifically raises the levels of Gi-coupled EP3 splice variants.

Conclusion: The present data indicate that the mitogenic action of low PGE2 doses in CRC cells is mediated via Gi-proteins, most likely through the EP3 receptor subtype, and is superimposed by a second, cAMP-dependent anti-proliferative effect at higher PGE2 doses. We discuss how these findings contribute to rationalize conflictive literature data on the proliferative action of PGE2.

MeSH terms

  • Apoptosis / drug effects
  • Caco-2 Cells
  • Cell Growth Processes / drug effects
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Cyclic AMP / metabolism*
  • DNA, Neoplasm / biosynthesis
  • Dinoprostone / pharmacology*
  • Dose-Response Relationship, Drug
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • HT29 Cells
  • Humans
  • Receptors, Prostaglandin E / agonists
  • Receptors, Prostaglandin E / antagonists & inhibitors
  • Receptors, Prostaglandin E / metabolism
  • Receptors, Prostaglandin E, EP3 Subtype

Substances

  • DNA, Neoplasm
  • PTGER3 protein, human
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP3 Subtype
  • Cyclic AMP
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Dinoprostone